Angiogenesis, the development of new vasculature from preexisting blood vessels, plays a critical role in many physiological processes and pathological events. An increased understanding of how angiogenesis is regulated in tissues would contribute to a variety of biological and medical areas. The extracellular matrix (ECM) and matricellular proteins found in the ECM function as important regulators of angiogenesis by their interaction with endothelial cells and the angiogenic factors that control blood vessel development. SPARC (secreted protein, acidic and rich in cysteine), a matricellular protein, has recently been shown to interact with and regulate the activity of vascular endothelial growth factor (VEGF), a primary stimulant of angiogenesis in both normal and pathological situations. An understanding of the proteins in the ECM that interact with VEGF and their ability to regulate VEGF activity would contribute to our understanding of VEGF-induced angiogenesis and its role in tissue homeostasis and pathology. In this application I will characterize further the interaction of SPARC and VEGF. The ability of SPARC to block VEGF from activating VEGFR1 an VEGFR2 will be determined and the ability of SPARC to regulate VEGF activities including: migration of endothelial cells, chemotaxis of macrophages, and vascular permeability will be examined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010352-02
Application #
6388772
Study Section
Pathology A Study Section (PTHA)
Program Officer
Schucker, Beth
Project Start
2001-06-01
Project End
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
2
Fiscal Year
2001
Total Cost
$40,196
Indirect Cost
Name
The Hope Heart Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98122
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Puolakkainen, Pauli A; Bradshaw, Amy D; Brekken, Rolf A et al. (2005) SPARC-thrombospondin-2-double-null mice exhibit enhanced cutaneous wound healing and increased fibrovascular invasion of subcutaneous polyvinyl alcohol sponges. J Histochem Cytochem 53:571-81
Puolakkainen, Pauli A; Brekken, Rolf A; Muneer, Sabeeha et al. (2004) Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res 2:215-24
Brekken, Rolf A; Sullivan, Millicent M; Workman, Gail et al. (2004) Expression and characterization of murine hevin (SC1), a member of the SPARC family of matricellular proteins. J Histochem Cytochem 52:735-48
Sweetwyne, Mariya T; Brekken, Rolf A; Workman, Gail et al. (2004) Functional analysis of the matricellular protein SPARC with novel monoclonal antibodies. J Histochem Cytochem 52:723-33
Koukourakis, Michael I; Giatromanolaki, Alexandra; Brekken, Rolf A et al. (2003) Enhanced expression of SPARC/osteonectin in the tumor-associated stroma of non-small cell lung cancer is correlated with markers of hypoxia/acidity and with poor prognosis of patients. Cancer Res 63:5376-80
Brekken, Rolf A; Puolakkainen, Pauli; Graves, David C et al. (2003) Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 111:487-95